PROJECT SUMMARY: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally, and in the US, where one-quarter of COPD occurs in non-smokers. Non-smokers represent 50% of the US population over 50 years old, but have been excluded from major COPD studies. In the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, we recently demonstrated that variant airway anatomy was common and associated with higher COPD prevalence. Findings were consistent among smokers and non- smokers but underpowered in the latter group. The current application would define the clinical significance of variant airway anatomy among non-smokers for COPD and respiratory symptoms, and for incident COPD and lung function decline over 10 years. Hypothesis 1: Variant airway anatomy is independently associated with COPD and respiratory symptoms cross-sectionally among 2,635 non-smokers and with incident COPD and decline in lung function among 2,000 non-smokers followed for a median of 10 years. Preliminary computational fluid dynamic (CFD) modeling suggests that variant airway anatomy may alter airway resistance and particulate matter transit to the distal airways. Additional pilot work suggests that these proximal airway variants may be markers of altered airway branching through the lung, suggesting a global increase in airway resistance with the variant applying to non-smokers. The current application would test if these mechanisms apply differentially to non-smokers and smokers to facilitate personalization of risk and care for COPD. Hypothesis 2: Mechanisms of COPD risk differ by common airway variant among non-smokers and smokers: 2a The accessory segmental airway variant, which is associated with increased risk among non- smokers, reduces regional airflow in a CFD model of participant-specific geometry, whereas the absent segmental airway variant, associated with increased risk among smokers, increases particulate transfer to the distal lung. 2b The accessory segmental airway variant is associated with globally altered airway branching, whereas the absent segmental airway variant represents lobe-specific altered airway branching. Airway anatomy has developmental origins and may provide a refined phenotype (compared to lung function) for genetic investigation. Preliminary analysis by the PI identified genetic variants in fibroblast growth factor 10, a gene implicated in airway development, to be associated with variant airway anatomy. The proposed study will increase the sample size 5-fold to perform the first genome-wide association study (GWAS) of variant human airway anatomy, with replication in an independent sample. Hypothesis 3: GWAS will discover genetic variants underlying the common airway variants, with replication in an independent sample. The current application represents the largest structure-function evaluation of COPD among non-smokers; and will test developmental and biological hypotheses to identify novel preventative and therapeutic strategies for this understudied but majority subgroup of the US population.